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. Author manuscript; available in PMC: 2009 Feb 12.
Published in final edited form as: Org Lett. 2008 Mar 7;10(7):1421–1424. doi: 10.1021/ol8001865

A Multifaceted Phosphate Tether

Application to the C15-C30 Subunit of Dolabelides A-D

Alan Whitehead 1, Joshua D Waetzig 1, Christopher D Thomas 1, Paul R Hanson 1
PMCID: PMC2641022  NIHMSID: NIHMS48379  PMID: 18324822

Abstract

Construction of the C15-C30 subunit of dolabelide utilizing a temporary phosphate tether is described. Two routes are reported that make use of the orthogonal protecting- and leaving-group properties innate to phosphate esters. One route relies on a selective terminal oxidation, while a second utilizes a CM/selective hydrogenation sequence. Both routes depend on a highly regio- and diastereoselective cuprate addition to set the requisite stereochemistry at C22.

Dolabelide A and B1 are 22-membered macrolides collected and characterized from the sea hares Dolabella auricularia. Upon further investigation of these extracts, researchers uncovered two additional 24-membered macrolide analogs of dolabelide A and B and termed them dolabelide C (1) and D (Scheme 1).2 Dolabelides A-D show cytotoxicity against human cervical cancer HeLa-S3 cells with IC50 values of 6.3, 1.3, 1.9, and 1.5 μg/mL, respectively. Despite this promising activity, their mechanism of action remains unknown. The biological activity and stereochemical complexity of this family present worthy and formidable synthetic challenges and warrant continued synthetic studies directed at this family of macrolides.

Scheme 1.

Scheme 1

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Retrosynthetic Analysis of Dolabelide C

Several synthetic studies3 have recently been reported for the dolabelide family, including one total synthesis of dolabelide D by Leighton and co-workers in 2006.4 Among these efforts, two reports toward the C15-C30 fragment have been presented, with Leighton and co-workers publishing the only complete C15-C30 fragment bearing the requisite stereochemistry.3d

Retrosynthetic analysis reveals a logical disconnection at C1-C14 and C15-C30 (2, Scheme 1) for the entire family of dolabelides. A key acid coupling between the C1 carboxylic acid and either the C23 or C21 carbinol centers will serve to join the two major subunits. Subsequent RCM macrocyclization, following the precedent established by Leighton4 will deliver the C14/C15 trisubstituted olefin moiety.

Convergent assembly of the C15-C30 subunit via the C23-C24 bond is envisioned to occur through vinylate coupling of metalated 3 with aldehyde 4 (Scheme 1). The 1,3-anti diol moiety contained within subunit 2 (C19 and C21) can be derived from phosphate triester building block (S,S)-5,5 assembled via phosphate tether mediated desymmetrization of C2-symmetric anti-diol (S,S)-6. The complimentary phosphate tether approach to the C1-C14 subunit of the dolabelide family has been recently reported and highlights a cross-metathesis and phosphate-mediated regioselective olefin transposition strategy emanating from (R,R)-5.6 Herein we report ongoing progress toward the dolabelide family of macrolides through preparation of the C15-C30 subunit.

Initial efforts toward the construction of the C15-C30 subunit of dolabelide began with the enantiomeric bicyclic phosphate (S,S)-5 (Scheme 2). Mild NaBO3 oxidation conditions were employed following a chemoselective hydroboration of the exocyclic olefin of (S,S)-5. A perborate oxidation protocol developed by Burke and co-workers was implemented7 and optimized for bicyclic phosphate 5. Yields in this study were highly dependent on the amount of oxidant, equivalents of H2O, and reaction time. Subsequent PMB ether formation using the p-methoxybenzyl trichloroacetimidate of PMBOH produced 7 in good yields and highlights the acid stability of bicyclic phosphate (S,S)-5. A regio- and diastereoselective SN2′ cuprate addition5 to 7 followed by methylation (TMSCHN2 and MeOH) afforded cyclic phosphate ester 8 in excellent overall yield (87%, ds = >95:5). The unique orbital alignment within bicyclic phosphate 7, in synergy with its concave nature, dictates the high selectivity in this SN2′ cuprate reaction.8

Scheme 2.

Scheme 2

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Synthesis of Aldehyde 11

The remaining steps to aldehyde 11 were non-problematic and involved an intitial reductive cleavage of the monocyclic phosphate ester with LiAlH4 in Et2O to provide diol 9 as a single diastereomer in excellent yield (96%). Quantitative acetonide formation and subsequent ozonolysis afforded 11a in good yield. Alternatively, selective mono-TIPS protection (9, TIPSCl, imidazole, rt)9 followed by MOM protection and ozonolysis produced 11b in good to excellent yields over three steps.

Construction of the C24-C30 vinyl iodide fragment 13 was achieved in two steps from known 12 (Scheme 2).3d Alkyne 12 was produced from commercially available R-(-)-epichlorohydrin, employing the Yamaguchi protocol for oxirane alkynylation.10 Subsequent zirconocene-promoted carboalumination, utilizing Wipf’s water-accelerated procedure11 and iodine quench, provided trisubstituted vinyl iodide in 61% yield. Methylmethoxy (MOM) protection ultimately afforded 13 in >95% yield.

With 11a/11b and vinyl iodide 12 in hand, methods for the construction of both the C23-C24 C-C bond and C23 stereochemistry were investigated (Scheme 3). Reaction of acetonide-protected 11a with the lithium-halogen exchange metalate of 13 (tBuLi, -78 °C to rt) or the vinyl Grignard of 13 (tBuLi, -78 °C, MgBr2·Et2O) provided Felkin C22/C23-syn selectivity of the undesired C21-C23 1,3-anti product 14a in modest diastereoselectivity (2-4:1 dr). Selectivity for the undesired C23 epimer was highest when employing Oshima protocol12 using vinyl magnesiate formation in the presence of MgBr2·Et2O, where selectivities of ∼8:1 were observed in favor of the undesired C23 epimer, 1,3-anti-14a.13

Scheme 3.

Scheme 3

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Asymmetric Vinylate Additions into 11a/11b

To circumvent this selectivity issue we employed reagent controlled asymmetric addition to 11b using Oppolzer’s zinc vinylate-lithium alkoxy N-methylephedrine complex14 recently described by Marshall15 and co-workers for vinylate additions to α-chiral aldehydes. Under these conditions 14b was formed in an 11:1 ratio of diastereomers favoring the desired C21-C23-syn product in moderate yield.

Despite this success, difficulties in reaction reproducibility (also recently noted by Marshall)16 and low product yields prompted investigation of an alternative oxidation/hydride reduction sequence for the formation of the requisite 1,3-syn diol within 14. Thus, Dess-Martin periodinane oxidation of the C23 epimers of 14b, followed by reduction of the resulting ketone using Suzuki’s 1,3-syn selective, chelation-controlled reduction conditions (LiAlH4, LiI)17 afforded the desired 1,3-syn diastereomer (14b) as a 4.3:1 mixture of diastereomers in 90% yield.18

With 14b in place, only the installation of the C14-C15 terminal olefin was needed to complete the C15-C30 subunit of dolabelide. Following MOM-protection of the C23 alcohol (15), DDQ removal of the PMB ether proceeded in good yield to afford alcohol 16 (Scheme 5). Tosylation of the primary alcohol provided 17 in 90% yield. Treatment of 17 with an allyl Grignard in the presence of stoichiometric CuI led to the formation of allylated product 18 in 89% yield. Overall, the sequence represents a 12-step synthesis to 18 from 5, bearing the requisite stereochemistry for the C15-C30 subunit of dolabelide.

Scheme 5.

Scheme 5

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Completion of the C15-C30 Subunit of Dolabelide

An alternative approach to the C15-C30 side chain was additionally investigated employing previously established cross metathesis (CM) methodology (Scheme 6).5c As anticipated, 5 underwent CM with 19 in the presence of 6 mol % H-G catalyst19 in DCE (90 °C) providing E-configured 20 in 82% yield (>95:5, E:Z).5c Selective reduction of the external olefin was achieved with o-nitrobenzenesulfonylhydrazine,20 which provided 21 in (>95:5) regioselectivity and 75% yield.21 Regio- and diastereoselective methyl cuprate addition into 21, under the aforementioned conditions, followed by phosphate tether removal afforded diol 22 in good yield.

Scheme 6.

Scheme 6

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CM Route to the C15-C30 Subunit of Dolabelide

Aldehyde 24 was rapidly accessed using a three-step TIPS-MOM-ozonolysis sequence (Scheme 6). Lithiate addition into aldehyde 24 produced 25 as a 1:1 mixture of C23 epimers in 70% yield (Scheme 6). Subsequent employment of the aforementioned oxidation/Suzuki reduction conditions generated the desired diastereomer of 25 in 92% yield (ds) 5:1 at C23).17 Substrate 25 was MOM-protected and the PMB-ether removed using DDQ to produce primary alcohol 26. Iodination of the C14 primary alcohol occurred in 83% yield, followed by facile E2 elimination of a primary iodide in the presence of tBuOK (THF, 30 min, rt) afforded 18, in 92% yield. Given the success, and convenience of the alternative elimination approach to the C14/C15 olefin, we are currently investigating selective vinylate addition with 24 for stereocontrolled formation of C23 within 25.

In conclusion, we have successfully completed the synthesis of the C15-C30 subunit of dolabelides A-D using two routes relying on a temporary phosphate tether methodology developed in our laboratories. Both pathways make use of the orthogonal protecting- and leaving-group properties innate to phosphate esters. Ongoing efforts toward the completion of dolabelide are currently in progress and will be reported in due course.

Supplementary Material

Supporting Inf

Acknowledgment

This investigation was supported by funds provided by NSF CHE-0503875, NIH RO1 GM077309, and the NIH Dynamic Aspects in Chemical Biology Training Grant (A.W., J.D.W.). The authors would also like to thank Materia for supplying metathesis catalyst.

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Scheme 4.

Scheme 4

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Construction of Alcohol 14b

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supporting Inf
NIHMS48379-supplement-Supporting_Inf.pdf (25MB, pdf)

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